Successful corticosteroid therapy for severe liver injury secondary to herbal traditional Chinese medicine, Mega Defends X, assessed for causality by the updated RUCAM: A case report

Rationale: In China, herbal traditional Chinese medicine products are readily obtained without any requirement of prescription and widely used in real life, thereby increasing the incidence of their related herb-induced liver injury (HILI). However, the diagnosis of HILI is still challenging because its clinical manifestations are variable due to lack of any specific biomarkers. Misdiagnosis and inappropriate treatment may result in the progression of HILI. Patient concerns: A 55-year-old female patient was admitted to the hospital due to progressive jaundice. Diagnoses: The diagnoses of HILI secondary to Mega Defends X, an herbal traditional Chinese medicine product, for which the score was 9 based on the updated Roussel Uclaf Causality Assessment Method of 2016. Interventions: The patient received corticosteroid with a stepwise dosage reduction. Outcomes: The liver injury significantly improved by corticosteroid treatment. Lessons: Corticosteroids should be potentially effective and safe in patients with severe HILI.


Introduction
As the key metabolic center of chemical ingredients found in herbal products, the liver is particularly susceptible to adverse toxic reactions including herb-induced liver injury (HILI). [1]n a Chinese retrospective study on 1985 drug-induced liver injury (DILI) and HILI cases observed between 2009 and 2014, as much as 563 cases (28.4%) were HILI. [2]Once HILI is diagnosed, suspected herbs should be withdrawn according to the current practice guidelines. [3]Most of patients will recover spontaneously within 6 months of herb withdrawal.However, some patients will progress to chronic liver injury, acute liver failure (ALF), and even death. [4]A meta-analysis found that 1.5% of the 936 cases with confirmed HILI developed chronic liver injury and 10.4% died. [5], RW, RT, and SJ contributed equally to this work.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
The authors have no funding and conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee(s) and with the Helsinki Declaration (as revised in 2013).Prescription and non-prescription conventional drugs are common causes of DILI.As opposed, herbal products are causes of HILI with clear different features compared with DILI. [6]We report the clinical course in a case of severe HILI secondary to Mega Defends X, an herbal product of traditional Chinese medicine, with focus on the effectiveness of corticosteroid therapy and causality assessing approach.
On April 22, TBIL was 450.8 μmol/L, ALT was 498.25 U/L, AST was 772.46 U/L, ALP was 84.90 U/L, GGT was 133.38 U/L, ALB was 31.1 g/L, and INR was 1.18, indicating a deterioration of HILI (Fig. 1).At the same day, methylprednisolone was intravenously given at a dosage of 40 mg/d.On April 25, TBIL was 262.10 μmol/L, ALT was 426.50 U/L,  AST was 341.61 U/L, AKP was 85.51 U/L, and GGT was 237.14 U/L (Fig. 1).On May 10, TBIL was 48.30 μmol/L, ALT was 59.63 U/L, AST was 27.55 U/L, ALP was 45.24 U/L, GGT was 188.23 U/L (Fig. 1).Then, she was discharged.The dosage of methylprednisolone was gradually reduced for 2 weeks and completely stopped 3 months after discharge.Liver tests remained normal during a 15-month follow-up period.

Discussion
Herbal products are often considered to be safe, but carry a potential risk of damage to the liver and other organs. [8]In our case, other definite causes of liver injury were excluded based on clinical history, laboratory examinations, and imaging findings.After reviewing the instructions, Mega Defends X is an herbal product, consisting of vitamins C, B1, B2, B6, B12, and  * Adapted from an open access report on the updated RUCAM [7] .† Each drink was 10 g ethanol.
E, selenium, coenzyme Q10, baicalin, and catechin.Notably, baicalin and catechin may cause significant liver injury. [9,10]owever, Puri et al found that liver injury may not be related to baicalin, but other drugs concomitantly taken, after reviewing the cases of liver injury induced by baicalin. [11]In addition, Puri et al also assessed the change of liver function in patients on long-term baicalin administration and suggested no evidence about hepatotoxicity of baicalin. [11]Indeed, the United States Pharmacopeia deemed that the occurrence of severe hepatotoxicity might be associated with catechin. [12]But hepatotoxicity may be idiosyncratic, but not dose-dependent. [13]Besides, pesticide residues and bacterial contamination in the production process of herbal products may also cause liver injury. [13]Finally, we suspected that the use of Mega Defends X is the highly probable source of the liver injury.Currently, it is still challenging to make an accurate diagnosis of HILI.This might be due to the absence of specific biomarkers and manifestations for diagnosis of HILI.Its diagnosis is primarily based on the disease course after exclusion of other liver diseases. [7]The challenge period from initial ingestion of suspected herb products to the onset of HILI can range from a few days to months, and HILI mostly occurs in the first 3 months of ingestion. [6]As a well-known scale for diagnosis of HILI, RUCAM includes 7 different domains, and provides a framework for a more objective evaluation in suspected cases of HILI.The causality between suspected herbal products and liver injury is classified into highly probable (score ≥ 9), probable (6-8), possible (3-5), unlikely (1-2), and excluded (≤0) based on the updated RUCAM score. [7]In our patient, the RUCAM score was 9, consistent with highly probable causality.
HILI can be classified into hepatocellular injury (R ≥ 5), cholestatic injury (R ≤ 2), and hepatocellular-cholestatic mixed injury (2 < R < 5). [7]The R value is defined as actual ALT/upper limit of normal divided by actual ALP/ upper limit of normal.The actual ALT and ALP should be initial. [14]In our patient, the initially actual ALT and ALP levels were 1492 U/L and 125.99 U/L, respectively.In our patient, the R score was 19.55, indicating hepatocellular HILI.Drugs should be selected according to the clinical pattern of HILI. [15]For hepatocellular HILI, a priority should be given to hepatoprotective drugs, including N-acetylcysteine, glutathione, magnesium isoglycyrrhizinate, and polyene phosphatidylcholine.For cholestatic injury HILI, a priority should be given to anticholestatic drugs, including ursodeoxycholic acid and S-adenosylmethionine. Our patient with hepatocellular HILI who presented with jaundice was initially treated with ademetionine 1,4-butanedisulfonate, polyene phosphatidylcholine, and glutathione.
According to the Chinese practice guideline, the severity of HILI was classified into 5 grades, including mild (TBIL > 42.75 μmol/L with INR < 1.5), moderate (TBIL > 42.75 μmol/L with INR ≥ 1.5), and severe liver injury (TBIL > 85.5 μmol/L with/ without INR ≥ 1.5), ALF (TBIL > 171 μmol/L with INR ≥ 2.0), and death. [14]At our patient's admission, TBIL level was 423.4 μmol/L, but INR was 1.11, which indicated severe liver injury.Silymarin, bicyclol, magnesium isoglycyrrhizinate, and N-acetylcysteine are often suitable for acute HILI. [16]If TBIL level was not reduced after regular therapy, corticosteroids would be considered. [17]However, the role of corticosteroid for HILI is controversial.Hou et al demonstrated that corticosteroid therapy group showed a higher rate of disease resolution and shorter recovery time, [18] which was similar to studies conducted by Niu et al [19] and Wang et al. [20] On the contrary, Karkhanis et al [21] found that corticosteroids did not improve overall survival of HILI patients.This might be primarily because nearly all included patients were diagnosed with ALF.The severity of HILI seems to influence the efficacy of corticosteroids.In our patient, methylprednisolone as intravenous infusion (40 mg/d) was given since prior treatment ademetionine 1,4-butanedisulfonate, polyene phosphatidylcholine, and glutathione was not effective.
A therapy with gradually tapering off the dosage of corticosteroid is recommended in clinical practice, because its abrupt withdrawal may result in the recurrence of the liver injury. [17]n our patient, the dosage of methylprednisolone was gradually reduced and completely stopped 3 months after discharge.Corticosteroids may cause infection, gastrointestinal bleeding, diabetes mellitus, hypertension, psychosis, moon face, and osteoporosis. [22]However, previous studies found that corticosteroids failed to increase the incidences of infection and gastrointestinal bleeding in patients with HILI. [21,23]Diabetes mellitus, psychosis, and hypertension also disappeared after withdrawal of corticosteroid. [24]Although the adverse events of corticosteroids are treatable, this should be kept in mind and take prompt interventions.Our patient did not develop any adverse events during treatment of the corticosteroid.The use of corticosteroid seems to be safe in our patient.

Conclusion
Our case report suggests the probability of developing HILI secondary to herbal products such as the traditional Chinese medicine, Mega Defends X.Therefore, herbal products should be taken cautiously.Corticosteroids are potentially effective and safe in patients with severe HILI.In future, randomized clinical trials are necessary to evaluate the efficacy and safety of corticosteroids for HILI.The updated RUCAM represents an important clinical framework for HILI diagnosis and helps physicians decide whether HILI is the most probable diagnosis.

Table 1
Detailed RUCAM score for our patient*.